It flows from the upper slopes of Bryn Garw in the Cambrian Mountains, through the Abergwesyn Valley, past the Nant Irfon National Nature Reserve in the hills above the village of Abergwesyn, and through Llanwrtyd Wells to its confluence with the River Wye at Builth Wells.

From its source at 540 metres (1,770 feet) AMSL on the upper slopes of Bryn Garw in the Cambrian Mountains the Irfon flows southwards past the foot of the Devil's Staircase, along the Abergwesyn Valley, through the scenic Camddwr Bleiddiad (Wolves' Gorge), and into the Wolves' Pool.

Lastly, overlooked by the scarp of Mynydd Epynt to the south, it flows eastward through Llangammarch Wells, and Garth to join the River Wye at Builth Wells (Llanfair ym Muallt) approximately 28 winding miles from its source.

The river is famous in Welsh history for the fact that it was on its banks, in the vicinity Cilmeri, that Llywelyn ap Gruffudd, Prince of Wales, was killed on 11 December 1282.

The Abergwesyn Valley and the legend of the boy failing to safely leap the Wolves' Gorge ('Camddwr Bleiddiad') were described by George Borrow in his 1862 travel publication Wild Wales: Its People, Language and Scenery.